Device for the detection of at least one ligand contained in a sample that is to be analyzed

ABSTRACT

Disclosed is a device for detecting at least one ligand contained in a sample that is to be analyzed. Said device comprises an optical waveguide, on the surface of which at least one ligand-specific receptor is directly or indirectly immobilized. The ligand bonds to said receptor during contact therewith. The inventive device comprises at least one optical source of radiation for injecting excitation radiation into the waveguide, the radiation being used for exciting emission of luminescence radiation in accordance with the bonding of the ligand to the receptor. At least one radiation receiver is integrated into the semiconductor substrate of a semiconductor chip so as to detect the luminescence radiation. The waveguide is integrated in a monolithic manner into the semiconductor substrate or is applied thereupon as a wave-guiding layer.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a device for the detection of at least oneligand contained in a sample that is to be analyzed, with an opticalwaveguide, on the surface of which at least one receptor is directly orindirectly immobilized which, when it comes into contact with theligand, forms a specific bond with the ligand, with at least one opticalsource of radiation for injecting excitation radiation into thewaveguide, the radiation being used to excite the emission ofluminescence radiation in accordance with the bonding of the ligand tothe receptor, and with a semiconductor chip that has at least oneradiation receiver on a semiconductor substrate to detect theluminescence radiation.

2. Description of the Prior Art

A similar device of the prior art is described in DE 100 02 566 A1. Onthe surface of a planar optical waveguide it has a plurality ofmeasurement points at which specific nucleic acids are immobilized inthe form of receptors. A liquid sample to be analyzed and that containsnucleic acids that are complementary to the receptors is placed incontact with the receptors. These nucleic acids bind to the specificreceptors to which they are complementary. The receptor-ligand complexesthat have nucleic acids that are complementary to each other are markedwith a luminescent substance. By means of a laser diode, for example, anexcitation radiation is generated and injected into the opticalwaveguide. An electromagnetic field, also called the evanescence field,is generated in a layer of the sample that is adjacent to the boundarysurface by total reflection on the boundary surface of the waveguide.This field penetrates into the liquid sample to a depth of only a fewhundred nanometers from the boundary surface. To emit luminescenceradiation, the evanescence field excites almost exclusively theluminescent substance that is bonded to the surface of the waveguide.For the detection of the nucleic acids that are contained in the sample,the luminescence radiation is detected by means of a CCD camera with ahigh degree of local resolution. The CCD camera is located on thereverse side of the waveguide facing away from the receptors. It has anoptical imaging system that images each of the individual measurementpoints located on the surface of the waveguide on the respectivedetector elements of a CCD sensor. The disadvantage of this device isthat it still has a relatively large number of system components and istherefore correspondingly complex and expensive. An additionaldisadvantage is that the device is relatively large. Finally, themeasurement sensitivity of the device leaves something to be desired.

The object of the invention is therefore to create a device of the typedescribed above which makes it possible to have a compact size with asimple and economical construction.

SUMMARY OF THE INVENTION

The invention teaches that the waveguide is monolithically integratedwith the semiconductor substrate or is located in the form of awaveguide layer on the semiconductor ship.

In that case, the at least one radiation receiver is located directly onthe back side of the waveguide facing away from the receptor, and isthus at an appropriately short distance from the at least one receptor.The result is a very compact and flat device, which can have the shapeof a wafer, for example. On account of the short distance between thereceptor and the radiation receiver, there is no need for a complex andexpensive optical imaging system between the receptor and the radiationreceiver. The luminescence radiation emitted by a luminescent substancethat has been deposited on the receptor can be detected over a largesolid angle segment. The result is a device with a simple constructionthat can be manufactured economically and has high measurementsensitivity. The term “luminescence” as used here means all luminousphenomena such as fluorescence or phosphorescence that substancesexhibit after quantum excitation.

In one preferred embodiment of the invention, the waveguide extends toover at least one radiation receiver, whereby the at least one receptoris preferably located on the surface of the waveguide directly oppositethe radiation receiver. In that case, the luminescence radiation emittedby a ligand that is bonded to the receptor or by a luminescent substancelocated on the receptor runs approximately orthogonally to the directionof extension of the waveguide, which achieves an effective transmissionof the luminescence radiation through the waveguide into the radiationreceiver. The luminescence radiation is therefore conducted directly tothe radiation receiver without detours or bypasses, as a result of whicha high detection sensitivity of the device is made possible.

It is advantageous if the waveguide layer is directly adjacent to thesemiconductor chip, and if the topography of the semiconductor chip inthe area of the semiconductor chip directly adjacent to the waveguide isrealized so that the boundary surface opposite the at least one receptorbetween the semiconductor chip and the waveguide runs between two planesthat are oriented parallel to the plane of extension of thesemiconductor chip and the distance between said two planes is less thanthe wavelength of the excitation radiation, and in particular less thanone-half, preferably one-quarter and optionally one-eighth of thewavelength of the excitation radiation. In the vicinity of thewaveguide, therefore, the topography of the semiconductor chip isessentially plane, which makes possible a low-loss guidance of theexcitation radiation in the waveguide. In a corresponding manner, theboundary surface of the waveguide that faces the receptors can also runbetween two planes that are oriented parallel to the plane of extensionof the semiconductor chip, whereby the distance between said planes isless than the wavelength of the excitation radiation, and in particularless than one-half, preferably one-quarter and optionally one-eighth ofthe wavelength of the excitation radiation. The semiconductor chip canhave an oxide layer at the boundary surface to the waveguide.

In one advantageous embodiment of the invention, located between thesemiconductor chip and the waveguide is an intermediate layer, theoptical index of refraction of which is less than that of the waveguide,whereby the intermediate layer has the negative shape of the surfacestructure of the semiconductor chip on its back side facing thesemiconductor chip and on its back side which is in contact with thesemiconductor chip, and whereby the front side of the intermediate layerthat forms the boundary surface with the waveguide is plane. It isthereby even possible for the waveguide to extend continuously orwithout interruption over the at least one radiation receiver and/or thestructures for the electronic circuit. During the manufacture of thedevice, the intermediate layer is preferably produced by firstfabricating the semiconductor chip with the at least one radiationreceiver and then optionally the structures for the electronic circuiton a wafer, and then depositing on the wafer a liquid medium containingthe material for the intermediate layer using a centrifuge process.After the medium has been uniformly distributed on the wafer by thecentrifugal force, it solidifies to form the intermediate layer. Thewaveguide is then deposited on top of it. The medium can contain avolatile solvent such as toluene, for example, and a polymer such asPMMA, for example. Spin-on glass can also be used as the liquid medium,however.

In one advantageous embodiment of the invention, the intermediate layeris realized in the form of an adhesive layer, preferably in the form ofa polymer layer. In that case, the waveguide can then be manufacturedeconomically and in large quantities in the form of an injection-moldedplastic part. The waveguide can be a thin plastic or glass wafer whichis adhesively attached to the semiconductor substrate during themanufacture of the device. The waveguide can also serve as a protectivecover for the semiconductor chip. The waveguide can optionally extendover the entire semiconductor chip.

In an additional realization of the invention, the waveguide isconnected with the semiconductor chip by means of at least one bondingpoint. In this embodiment, too, the waveguide can be a thin plasticwafer that is preferably less than one millimeter thick.

In one advantageous realization of the invention, the waveguide isrealized in the form of a thin-film coating which is preferably made ofa transparent polymer, and in particular polystyrene. The at least onereceptor is thereby preferably located directly on the thin-film layer.However, the waveguide can also be made of another material, for examplespin-on glass. Using thin-film technology, the waveguide can bemanufactured so that it is less than 100 micrometers thick. Therefore, acorrespondingly large percentage of the luminescence radiation emittedby the luminescent substance bonded to the receptor will then strike theradiation receiver. For the detection of the ligands in the sample, onlya small amount of the sample is therefore required. For the manufactureof the device, the waveguide can be deposited in a simple manner on thewaveguide by immersion-coating or using the centrifuge method.

In one particularly advantageous embodiment of the invention, thewaveguide is also formed by a metal oxide layer, in particular a silicondioxide (SiO₂) layer or a tantalum pentoxide (Ta₂O₅) layer. In thatcase, the waveguide can be manufactured economically using standardprocesses for semiconductor manufacturing, such as plasma oxidation orchemical vapor deposition (CVD), for example. The thickness of thewaveguide can thereby be less than 10 micrometers, so that almost halfof the luminescence radiation emitted by a luminescent substance bondedto the surface of the waveguide strikes the radiation receiver. Theresult is a correspondingly high measurement sensitivity, which meansthat only extremely small quantities of sample material are required foran analysis of the sample. The oxide layer can have a surface structureto which at least one receptor adheres directly. Consequently there isno longer any need for a layer of adhesion promoter between thewaveguide and the at least one receptor. It is also possible, however,for the waveguide to be realized in the form of a silicon nitride(Si₃N₄) layer.

It is particularly advantageous if the optical radiation source isrealized in the form of a semiconductor radiation source and isintegrated into the semiconductor chip. In that case, the device makespossible an even more compact and economical construction. Thesemiconductor radiation source can be a laser diode or an LED that emitsthe excitation radiation preferably in a narrow-band wavelength range inwhich the at least one radiation receiver is insensitive.

In one preferred embodiment of the invention, for the injection of theexcitation radiation into the waveguide, an optical injection system isprovided in the emission area of the optical radiation source, and ispreferably realized in one piece with the waveguide and has, among otherthings, at least one prism, one optical lattice and/or a deflectingmirror. The radiation source can be located on the back side of the waveguide facing away from the receptors, with its emission side facing theoptical injection system of the waveguide. The excitation radiationemitted by the radiation source is thereby deflected by the opticalinjection system so that it enters into the waveguide at an angle whichis selected so that the radiation is guided by taking advantage of thetotal reflection in the waveguide. The result is a low-loss guidance ofthe excitation radiation from the radiation source to the at least onereceptor.

It is advantageous if a plurality of radiation receivers integrated intothe semiconductor substrate next to each other, preferably in the formof rows or a matrix, if at least one detection field that has at leastone receptor is located in the detection range of the individualradiation receivers. In that case, the device makes possible a detectionof the receptor-ligand complexes on the surface of the waveguide as wellas a resolution of their individual locations. The individual detectionfields can have different receptors, so that the sample can be testedsimultaneously for the presence of a plurality of different ligands. Itis also conceivable, however, that at least one group of detectionfields can have the same receptors. The measurements from the individualradiation receivers of the group can then be averaged, filtered and/orcompared to one another for control purposes. If the concentration ofthe ligand in the sample is to be determined by means of the device, itis advantageous if the receptors of at least two detection fields have adifferent affinity for the ligands. The concentration of the ligand canthen be measured in a broad concentration range, without having todilute or concentrate the sample to perform the measurement. Thewaveguide can extend over the radiation receiver without interruptionsor discontinuities, which means that a masking step can be eliminatedduring the manufacture of the waveguide.

The detection fields are thereby at some distance from one another andare positioned relative to the radiation receivers so that theindividual radiation receivers receive essentially no luminescenceradiation from a detection field of another radiation receiver. Thus ahigh crosstalk attenuation is achieved between the measurement systemsconsisting of the individual detection fields and the individualradiation receivers associated with each of them.

In one advantageous realization of the invention, the at least onereceptor is located in the interior cavity of a flow-through chamberthat has at least one inlet opening and one outlet opening, whereby thesemiconductor substrate preferably forms a wall area of the flow-throughmeasurement chamber. In the flow-through measurement chamber,biomolecules or biocomponents can then be tested and can be suppliedwith a nutrient fluid by means of the inlet and outlet openings. Thebiomolecules can be nucleic acids or derivatives thereof (DNA, RNA, PNA,LNA, oligonucleotides, plasmids, chromosomes), peptides, proteins(enzyme, protein, oligopeptiide, cellular receptor proteins andcomplexes thereof, peptide hormones, antibodies and fragments thereof),carbohydrates and derivatives thereof, in particular glycolized proteinsand glycosides, fats, fatty acids and/or lipids.

To control the temperature of the flow-through measurement chamber, aheating and/or cooling device can be provided which preferably has aPeltier element. The heating device is preferably realized in the formof a thin-film heater. The device can thereby be used for multiplepurposes by raising the temperature in the flow-through measurementchamber after a measurement to a point where all of the ligands bondedto the receptors are released from the receptors. In that case, theligands can also be flushed out of the flow-through measurement chamberby feeding in a flushing medium via the outlet opening. The flushingprocess is thereby continued until the radiation receivers no longerdetect any luminescence radiation. Then a new sample can be introducedinto the flow-through measurement chamber via the inlet opening andtested. However, the device can also be used for the determination ofthe melting point and/or the bonding constants of a ligand such as a DNAsequence, for example. The bonding of the ligand to the receptors isthereby measured as a function of temperature and/or time. The meltingpoint of the DNA sequence can also be determined from the melting curvemeasured as indicated above, i.e. the temperature at which one-half ofan originally double-stranded DNA sequence is present in the form of asingle strand. By means of the melting point it is possible to recognizemutations in DNA sequences which can occur in genetically transmittedillnesses, for example.

In one appropriate realization of the invention, at least one reagentand/or reaction partner is stored in the flow-through measurementchamber to detect the bonding of the at least one ligand to the at leastone receptor. The flow-through measurement chamber is then ready foruse, i.e. to perform the measurement, the only further action that isnecessary is to feed the sample to be tested into the measurementchamber via the inlet opening. The reagent and/or the reaction partneris preferably lyophilized and can be impressed on the inside wall of themeasurement chamber, for example. Preferably there is also a stabilizingagent such as trehalose, poly (2-hydroxyethyl) methacrylate (pHEMA) orbovine serum albumin (BSA).

Several exemplary embodiments of the invention are explained in greaterdetail with reference to the accompanying drawings, some of which arehighly schematic:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross section through a device for the detection of ligandscontained in a sample to be tested, with a flow-through measurementchamber.

FIG. 2 and FIG. 7 show a cross section through a wall area of theflow-through measurement chamber that has an optical waveguide, wherebyimmobilized on the waveguide are receptors to which ligands are bondedwhich are indirectly marked with a luminescent substance,

FIG. 3 is an illustration like the one presented in FIG. 2, whereby theluminescent substance is excited by means of excitation radiation toemit luminescence radiation, and whereby the excitation and theluminescence radiation are illustrated schematically in the form ofbeams,

FIG. 4 is an overhead view of a portion of a semiconductor chip,

FIG. 5 is a cross section through a portion of the semiconductor chipand the waveguide located on it, and

FIG. 6 is an illustration similar to the one in FIG. 5 although anintermediate layer is located between the waveguide and thesemiconductor chip.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

A device designated 1 overall for the detection of at least one ligand 2contained in an essentially liquid sample to be tested has asemiconductor chip 3 which is integrated using methods from thesemiconductor engineering industry with an optical waveguide 4 (FIG. 1).The waveguide can be made of a polymer material, for example.

FIG. 2 shows that on the surface of the waveguide 4, receptors 5 areimmobilized that, when they come into contact with the ligand 2, bind toit. The receptors can be immobilized by silanization, for example, or bya polyimide layer located on the waveguide 4, to which the receptorsadhere. The receptors 5 can be imprinted on the waveguide 4 on thepolyimide layer or on the polyimide layer located on the waveguide 4. Inthe exemplary embodiment illustrated in FIG. 2, the receptors 5 areantibodies to a specified epitope of the ligand 2. After the bonding ofthe epitope to the receptor 5, the antibody complex thus formed,consisting of the epitope and the receptor 5, is marked by means of asecond antibody 6 that bonds to the first epitope. This antibody 6 isdirectly or indirectly marked with a luminescent substance 7.

FIG. 1 shows that an optical semiconductor radiation source 8, such as alaser diode or LED, for example, is integrated into the semiconductorchip 3. The spectrum of the radiation 9 emitted by the radiation source8 has at least one excitation wavelength at which the luminescentsubstance 7 is excited to the emission of luminescence radiation 10. Forthe injection of the excitation radiation 9 into the waveguide 4, in theemission range of the radiation source 8 there is an optical injectionsystem 11, which has microprisms (not illustrated in any further detailin the drawing), which deflect the excitation radiation emitted by theradiation source 8 so that it is guided utilizing the total reflectionin the waveguide 4. As a result of the total reflection at the boundarysurface of the waveguide 4, an electromagnetic field is produced in theoptically thinner medium, namely the sample, as a result of which theluminescent substances 7 bonded to the surface of the waveguide 4 areexcited to emit luminescence radiation 10. Because the evanescence fieldpenetrates into the sample by a depth of only a few hundred nanometers,the luminescent substances 7 that are excited to emit the luminescenceradiation 10 are almost exclusively those on the surface of thewaveguide, while the unbonded luminescent substances 7 in the samplecontribute practically nothing to the luminescence radiation.

For the detection of the luminescence radiation there are a plurality ofoptical radiation receivers 12 integrated into the semiconductor ship 3,whereby all of the radiation receivers 12 are realized in the form ofsemiconductor components. The radiation receivers 12 are located on theback side of the waveguide 4, which is permeable to the luminescenceradiation 10 and faces away from the receptors 5. The luminescenceradiation 10 therefore strikes an optical imaging system on theradiation receivers 12 directly, i.e. without the interposition of anoptical imaging system. The device thereby has a compact and economicalconstruction.

The luminescent substance 7 is an upward-converting luminescentsubstance. Luminescent substances of this type are described in EP 0 723146 A1. Examples of upward-converting luminescent substances include theBND pigment by Dyomics GmbH, Jena, and IR-140. In contrast todownward-converting luminescent substances, upward-convertingluminescent substances do not acquire the energy needed for the quantumemission from a single quantum effect, but from multiple quantumeffects. Downward-converting luminescent substances, in comparison todownward [sic] converting luminescent substances therefore have asignificantly greater Stokes shift, at which the wavelength of theexciting radiation can be approximately twice as great, for example, asthe wavelength of the luminescence radiation. It is thereby possible toprovide, as the radiation source, an infrared semiconductor radiationsource 8 which makes possible a high level of radiation intensity withcompact dimensions. The infrared light from such semiconductor radiationsources 8 also has the advantage that fewer scatter effects occur thanwith short-wave optical radiation. By means of the upward-convertingluminescent substance 7, the optical radiation emitted by the radiationsource 8 can be converted into visible light or near-infrared light, towhich the radiation receivers 12 have a high detection sensitivity. Theradiation receivers 12 are insensitive to the excitation radiation 9.

FIGS. 2 and 3 show that the waveguide 4 extends to over the radiationreceiver 12 and that the receptors 5 are located on the surface of thewaveguide 4 directly opposite the radiation receiver 12. Thus theluminscence radiation 10 can travel directly from the luminescentsubstance 7 to the radiation receivers 12.

In the exemplary embodiment illustrated in FIGS. 4 and 5, the waveguide4 is directly adjacent to the semiconductor chip 3. The waveguide 4 hasinterruptions in which structures 13 for an electronic circuit arelocated. This circuit has printed conductors that are connected with theradiation receivers 12. The topography of the semiconductor chip in thearea of the semiconductor chip adjacent to the waveguide 4 is realizedso that the boundary surface 14 opposite the receptors 5 between thesemiconductor chip 3 and the waveguide 4 runs between two imaginaryplanes 14 a, 14 b that are each oriented parallel to the plane ofextension of the semiconductor chip 3, whereby the distance x betweensaid planes is less than one-eighth of the wavelength of the excitationradiation 9. This arrangement almost completely prevents an undesirablelight extraction out of the waveguide 4 at the boundary surface 14.Structures that require a surface topography of the semiconductor chip 3that is different from a plane, such as printed conductors made ofaluminum, for example, are essentially located laterally next to thewaveguide 4. In the exemplary embodiment illustrated in FIG. 5, thewaveguide 4 is formed by a semi-metal oxide layer, which extends over anarea near the surface on a semiconductor substrate 3 of thesemiconductor chip 3 and runs approximately parallel to the plane ofextension of the semiconductor substrate. The semiconductor substratecan be made of silicon, for example.

In the exemplary embodiment illustrated in FIG. 6, between thesemiconductor chip 3 and the waveguide 4, there is an intermediate layer15 that runs approximately parallel to the plane of extension of thesemiconductor chip 3 and the optical index of refraction of which isless than that of the waveguide 4. The intermediate layer 15 is directlyadjacent to the semiconductor chip 3 and has the negative shape of thesemiconductor chip 3. This shape can be achieved, for example, if thematerial for the intermediate layer 15 is deposited during themanufacture of the device 1 in liquefied form on the semiconductor chip3 using the centrifuge process and—after it has been distributeduniformly over the surface of the semiconductor chip 3—has solidified.On its side facing away from the semiconductor chip 3, the intermediatelayer 15 is flat. The waveguide 4 is deposited on the intermediate layer15 in the form of an additional layer. The result is a flat boundarysurface between the intermediate surface 15 and the waveguide 4, whichmakes possible a largely loss-free guidance of the excitation radiation9 in the waveguide 4. The waveguide 4 can thereby extend continuouslyover the semiconductor chip 3.

FIG. 1 shows that the radiation receivers 12 are connected by means ofprinted conductors with an actuator and analysis device 16 that isintegrated into the semiconductor chip. The analysis device 16 has aninterface device that is schematically indicated in the drawing forconnection with a higher-level display and/or analysis unit, such as amicrocomputer, for example.

FIG. 7 shows that a plurality of radiation receivers 12 are integratednext to one another in the form of a matrix in the semiconductorsubstrate. In the detection range of the individual radiation receivers12, each detection field is located with a plurality of receivers 5. Theindividual detection fields have different receivers 5, each of whichcan enter into a bond with a specified ligand 2.

In FIGS. 2 to 4, the receptors are shown on a larger scale than theradiation receivers 12. The distances between detection fields that arenext to one another on one hand and the distances between theluminescent substances 7 bonded to the receptors 5 and the radiationreceivers 12 associated with them are selected so that the individualradiation receivers 12 can receive essentially no luminescence radiationfrom a detection field of a neighboring radiation receiver.

FIG. 1 shows that the semiconductor chip 3 forms a wall area of aflow-through measurement chamber, in the interior cavity 17 of which thereceptors 5 are located. The flow-through measurement chamber has aninlet opening 19 and an outlet opening 18. The inlet opening 19 isconnected with a feed line for the sample, which is not shown in anydetail in the drawing, and the outlet opening 18 is connected with adischarge line.

It should also be mentioned that the radiation source 8 is connected,for the modulation of the excitation radiation 9, with a modulationdevice 20, which is integrated into the semiconductor chip 3. By meansof the modulation device 20, the excitation radiation 9 can be turned onand off in cycles, for example, to take into consideration in theanalysis any signal components that may be caused by spurious light ornon-specific optical excitation. For this purpose, the modulation device20 must be connected with the analysis device 16 by means of aconnecting line.

The device 1 for the detection of at least one ligand 2 contained in asample to be analyzed therefore has an optical waveguide 4, on thesurface of which at least one receptor 5 that is specific for the ligand2 is directly or indirectly immobilized. When the ligand 2 comes intocontact with the receptor 5, it bonds to the receptor. The device 1 hasat least one optical radiation source 8 for the injection of excitationradiation 9 into the waveguide 4. The radiation 9 is used to excite theemission of luminescence radiation 10 as a function of the bonding ofthe ligand 2 to the receptor 5. For the detection of the luminescenceradiation 10, at least one radiation receiver 12 is integrated into thesemiconductor substrate of a semiconductor chip 3. The waveguide 4 ismonolithically integrated with the semiconductor substrate or is appliedto the semiconductor substrate in the form of a waveguide layer.

1. A device for the detection of at least one ligand contained in asample that is to be analyzed, said device comprising: an opticalwaveguide defining a single light path along which multiple detectionfields and multiple radiation receivers are disposed, each detectionfield including at least one receptor for contacting a ligand to form aspecific bond with the ligand; at least one optical source of radiationfor injecting excitation radiation into the waveguide, the radiationbeing used for exciting the emission of luminescence radiation as afunction of the bonding of ligands to receptors; and a semiconductorchip having said radiation receivers on a semiconductor substrate, eachdetection field having one radiation receiver associated therewith, eachradiation receiver operative for detecting only the luminescenceradiation sent out by the detection field associated therewith, wherein:the waveguide is monolithically integrated with the semiconductorsubstrate or is in the form of a waveguide layer located on thesemiconductor chip; and the radiation receiver associated with eachdetection field is integrated into the semiconductor substrate facingthe detection field directly on the back side of the waveguide facingaway from the detection field.
 2. The device of claim 1, wherein thesemiconductor chip includes a boundary surface opposite the receptorsbetween the semiconductor chip and the waveguide, the boundary surfacerunning between two planes that are oriented parallel to the plane ofextension of the semiconductor chip, wherein the distance between thetwo planes is less than the wavelength of the excitation radiation. 3.The device of claim 2, wherein the distance between the two planes isless than either one-half, one-fourth or one-eighth of the wavelength ofthe excitation radiation.
 4. The device of claim 1, wherein thesemiconductor chip, laterally next to the waveguide, has an electroniccircuit.
 5. The device of claim 1, wherein: between the semiconductorchip and the waveguide there is an intermediate layer, the optical indexof refraction of which is less than that of the waveguide; a side of theintermediate layer adjacent the semiconductor chip conforms to a surfaceof the semiconductor chip; and a side of the intermediate layer adjacentthe waveguide is essentially plane.
 6. The device of claim 5, whereinthe intermediate layer is an adhesive coating.
 7. The device of claim 6,wherein the adhesive coating is a polymer coating.
 8. The device ofclaim 1, wherein the waveguide is connected with the semiconductor chipat least at one bonding point.
 9. The device of claim 1, wherein thewaveguide is a thin-film layer of a transparent polymer material. 10.The device of claim 9, wherein the polymer material is polystyrene. 11.The device of claim 1, wherein the waveguide is a metal oxide layer. 12.The device of claim 11, wherein the metal oxide layer is either asilicon dioxide layer or a tantalum pentoxide layer.
 13. The device ofclaim 1, wherein the optical radiation source is a semiconductorradiation source that is integrated into the semiconductor chip.
 14. Thedevice of claim 1, further including an optical injection systemprovided in the emission area of the optical radiation source fordeflecting optical radiation emitted by the optical radiation source tothe waveguide.
 15. The device of claim 14, wherein: the opticalinjection system is part of the waveguide; and the optical injectionsystem includes at least one of the following: a prism, an opticallattice and/or a deflecting mirror.
 16. The device of claim 1, whereinthe detection fields are spaced from one another and are positionedrelative to the radiation receivers so each radiation receiver receivesessentially no luminescence radiation from a detection field of an otherradiation receiver.
 17. The device of claim 1, wherein: the receptorsare located in an interior cavity of a flow-through measurement chamberthat has at least one inlet opening and one outlet opening; and thesemiconductor chip defines a wall area of the flow-through measurementchamber.
 18. The device of claim 17, further including a heating and/orcooling device for controlling a temperature of the flow-throughmeasurement chamber.
 19. The device of claim 18, wherein the heatingand/or cooling device is a Peltier element.
 20. The device of claim 17,wherein the flow-through measurement chamber includes at least onereagent and/or reaction partner for the detection of the bonding of atleast one ligand to at least one receptor.